Whole-genome sequencing (WGS) improves diagnostic accuracy in families with hypertrophic cardiomyopathy (HCM) compared with the use of targeted gene sequencing. Bagnall et al. used WGS to search for nucleotide variants in the coding regions of 184 genes, in deep intronic regions associated with RNA-splicing alterations and large genomic rearrangements, and in the mitochondrial genome in 58 patients with HCM, 14 affected family members, and two unaffected parents. WGS identified a plausible pathogenic variant in 20% of families for which previous genetic testing did not establish a molecular diagnosis. The identified variants were located in genes not included or filtered out in previous genetic testing, in noncoding regions, and in the mitochondrial genome. WGS also identified a pathogenic variant in 42% of families with no prior genetic testing. Thus, use of WGS might lead to improved diagnosis, family screening, and management of HCM.